Efficacy And Safety Of Lacosamide As Adjunctive Therapy In Adults With Focal-onset Epilepsy: A Meta-analysis

Objective:To evaluate the efficacy,safety and tolerability of lacosamide as adjunctive therapy for focal-onset epilepsy in adults.Methods:We searched PubMed,Embase,CENTRAL,CNKI,VIP,WANFANG,CBM,ClinicalTrials.gov and Chinese Clinical Trial Register(ChiCTR)in March 2019 for all randomized controlled trials(RCTs)of add-on lacosamide therapy in adults with focal-onset seizures.Two review researchers independently assessed trials for inclusion and extracted the relevant data.The Meta-analysis was performed on Stata 13.0 software.The outcomes include the proportion of patient who experienced 50% or greater reduction in seizure frequency(50% responder rate),the proportion of patients who achieved seizure-free status(seizure freedom),the proportion of patients who withdraw due to treatment-emergent adverse events(withdrawals due to TEAEs),the proportion of patients experienced serious adverse events(SAEs)and any TEAEs.This systematic review was divided into two parts.The first part was a Meta-analysis comparing the efficacy and safety of lacosamide with placebo.The second part was a Meta-analysis comparing the efficacy and safety of different doses of lacosamide.Results:We included four trials with 1856 participants in our systematic review after rigorous screening.The results of two-part meta-analysis were as follows.(1)The 50% responder rates [RR=1.85,95%CI(1.56,2.21),P<0.001],seizure freedom [RR=4.03,95%CI(1.52,10.70),P=0.005],withdrawals due to TEAEs [RR=2.54,95%CI(1.53,4.23),P<0.001] and SAEs [RR=1.79,95%CI(1.07,3.00),P =0.026]were significantly higher in lacosamide compared with that of placebo.(2)Compared with placebo,lacosamide 200mg/d was significantly higher in 50% responder rates [RR=1.60,95%CI(1.30,1.99),P<0.001],seizure freedom[RR=3.70,95%CI(1.24,11.04),P=0.019].There were no significant differences in withdrawals due to TEAEs and SAEs between the two groups.Compared with placebo,lacosamide 400mg/d was significantly higher in 50% responder rates [RR=2.00,95%CI(1.66,2.41),P<0.001],seizure freedom [RR=4.26,95%CI(1.53,11.83),P=0.005],withdrawals due to TEAEs[RR=2.99,95%CI(2.02,4.43),P<0.001] and SAEs [RR=2.15,95%CI(1.24,3.73),P=0.006].Compared with placebo,lacosamide 600mg/d was significantly higher in 50% responder rates [RR=1.98,95%CI(1.43,2.73),P<0.001] and withdrawals due to TEAEs [RR=5.72,95%CI(3.10,10.87),P<0.001].There were no significant differences in seizure freedom and SAEs between the two groups.(3)Compared with lacosamide 200mg/d,lacosamide 400mg/d was significantly higher in 50% responder rates [RR=1.23,95%CI(1.05,1.45),P=0.012] and withdrawals due to TEAEs [RR=2.43,95%CI(1.62,3.63),P<0.001].There were no significant differences in seizure freedom and SAEs between the two groups.Compared with lacosamide 400mg/d,lacosamide 600mg/d was significantly higher in withdrawals due to TEAEs [RR=1.55,95%CI(1.12,2.15),P=0.009].There were no significant differences in 50% responder rates,seizure freedom and SAEs between the two groups.(4)TEAEs significantly associated with lacosamide 200mg/d were diplopia,vertigo,dizziness and somnolence.TEAEs significantly associated with lacosamide 400mg/d were ataxia,diplopia,dizziness,vomiting,vision blurred,nausea,somnolence and headache.TEAEs significantly associated with lacosamide 600mg/d were ataxia,diplopia,vomiting,dizziness,blurred vision,fatigue,nausea and nystagmus.All of these TEAEs were dose-related except for somnolence,vertigo,headache and nausea.Every dose of lacosamide wasn’t associated with upper respiratory tract infection,accident not otherwise specified,tremor and rash compared with placebo.Conclusion:Based on current evidence,this systematic review and meta-analysis indicated that adjunctive therapy of LCM in adults with focal epilepsy could reduce seizure frequency and achieve seizure-free,which was of dose-related tolerability.LCM 200mg/day was of better tolerability,while LCM 400mg/day of better efficacy.LCM 600 mg/day failed to be more effective and was with a risk of poorer tolerability.Serious AEs were not found to be doserelated.More RCTs were required to confirm our conclusion.